The cytokine IL-21 signals through a heterodimeric receptor consisting of the common gamma chain and IL-21-specific receptor called “IL-21 receptor” or “IL-21R.” IL-21 receptor is expressed on a number of types of cells of the immune system, including dendritic cells, macrophages, NK cells, B cells, and CD4+ CD8+ T cells. With respect to T cells, IL-21 signaling stimulates CD8+ T cell proliferation and expansion. It causes naïve T cells to differentiate into Th17 cells, which it stabilizes and maintains. IL-21 signaling also down-regulates induced regulatory T cells and inhibits the suppressive effects of Tregs. Pathologic autoantibodies can be produced in germinal centers, the formation of which depends on IL-21 signaling. IL-21 also affects B cell activation plasma cell differentiation.
IL-21 signaling is associated with several pathologic conditions. Elevated levels of IL-21 are found in the sera of systemic lupus erythematosus (SLE) patients. Polymorphisms in IL-21 and IL-21 receptor have been implicated in increased susceptibility to developing SLE. Mouse models of SLE further implicate a role for IL-21 signaling.